tbuckley/cabot-search huggingface dataset:
Abstract 3679: A qualitative analysis of coping with genetically exacerbated risk of breast and ovarian cancers among medically-underserved women with <i>BRCA1/2</i> mutations
Authors: Kristi Tredway, Kate E. Dibble, Avonne E. Connor
Journal: Cancer Research (2022)

Abstract Individuals testing positive for BRCA1/2 genetic mutations, or hereditary breast and ovarian cancer mutations, are 33-55% more likely than women without these mutations to develop breast and/or ovarian cancers before the age of 70. While research involving these genetic mutations continues to emerge, there remains unanswered questions regarding prophylactic experiences and subsequent impacts on mental health within subgroups of BRCA1/2-positive women. The purpose of this analysis was to explore the impact of BRCA1/2 mutations, prophylactic surgeries, and surveillance regimens within the scope of everyday life within a sample of BRCA1/2 positive women from medically-underserved backgrounds living in the United States (US). A sample of 211 US adult women who have tested positive for BRCA1/2 mutations within the past 5 years and who identify with one or more medically-underserved populations (racial, ethnic, or sexual minority, person with a physical disability, chronically-ill, those in poverty, immigrant populations) elucidated compelling qualitative data. A total of 169 (80.1%) women completed open-ended questions at the end of the online survey. Thematic analysis was utilized to identify themes and subthemes concerning mental health, sources of stress, and methods of stress relief. The focus of the current analysis is on the sources of stress identified by the respondents. Fourteen subthemes were identified. The four most common stressors were concerns about post-treatment recovery (19% of respondents), recurrence of a new cancer (15%), medical unknown of having a genetic mutation that increases the risk of cancer (14%), and having to schedule and plan for continual surveillance (12%). The next five subthemes ranged from 7-9% and include waiting for medical results, personal finances and covering medical expenses, impact of the COVID-19 pandemic, pre-operative anxiety, and worrying about insurance coverage. Our findings support previous research on cancer stressors for women while adding important qualitative elements for a richer understanding. Furthermore, since much of the research on the lived experiences of BRCA1/2 has been on highly-educated, non-Hispanic white women, few studies have focused entirely on medically-underserved populations, which was the entirety of our sample. This work adds an important intersectional lens in which to better understand the experiences of living with a BRCA1/2 mutation. Citation Format: Kristi Tredway, Kate E. Dibble, Avonne E. Connor. A qualitative analysis of coping with genetically exacerbated risk of breast and ovarian cancers among medically-underserved women with BRCA1/2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3679.
Abstract LB005: ATAK receptors, a new class of chimeric antigen receptors that harness innate immunity in myeloid cells to target cancer
Authors: Neha Diwanji, Kyong-Rim Kieffer-Kwon, Thomas Prod’homme, Bruce McCreedy, Yuxiao Wang, Daniel Getts
Journal: Cancer Research (2022)

Abstract For the majority of patients with advanced solid tumors, sustained clinical benefit with immunotherapy has yet to be achieved. Myeloid cells, including monocytes and macrophages are the primary orchestrators of immune responses and are found to accumulate in tumors, in some cases contributing up to 75% of the tumor mass. Myeloid cells express a wide range of innate immune sensors such as Toll-like receptors, RIG-I and cGAS-STING as well as co-stimulatory molecules like CD40. The activation of these innate immune pathways in myeloid cells can associated with anti-tumor immune response. Notwithstanding the ability of the myeloid cells to infiltrate tumors and elicit broad immune responses, technologies capable of harnessing these cells to target cancer remains elusive. Here we designed and engineered a new class of chimeric antigen receptors that couple tumor recognition with multiple innate immune signal domains, referred to as Activate, Target, Attack &amp; Kill (ATAK) receptors. By combining cancer recognition domains with intracellular signaling domains from innate immune receptors such as Fc, TLR and cytokine receptors, we show that myeloid cells can be controlled and programmed to recognize cancer and elicit a broad and tunable immune response. Critically, in mice with established, highly immunosuppressive B16 melanoma tumors, delivery of monocytes engineered to express ATAK receptors results in anti-tumor activity. Our data show the versatility of building ATAK receptors by harnessing innate immune pathways and support their clinical development in cell therapies. Citation Format: Neha Diwanji, Kyong-Rim Kieffer-Kwon, Thomas Prod’homme, Bruce McCreedy, Yuxiao Wang, Daniel Getts. ATAK receptors, a new class of chimeric antigen receptors that harness innate immunity in myeloid cells to target cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB005.
Cover Image, Volume 42, Issue 6
Authors: Yang Xu, Ping Li, Yang Liu, Dijia Xin, Wen Lei, Aibin Liang, Weidong Han, Wenbin Qian
Journal: Cancer Communications (2022)

The cover image is based on the Review Article Epi-immunotherapy for cancers by Wenbin Qian et al., https://doi.org/10.1002/cac2.12313.
Abstract 5867: Examination of race/ethnicity differences in patient reported outcomes (PROs) among elderly female breast cancer patients in the SEER-MHOS database
Authors: Kendra R. Krebsbach, Chloe L. Stallion, Keith A. Dookeran
Journal: Cancer Research (2022)

Abstract We use regression models to examine baseline differences in physical and mental health PROs [Physical and Mental Component Summary T-scores (PCS/MCS: are linear transformations of the 0-100 possible range scoring for 8 SF-36/VR-12 sub-scales, with mean of 50 and standard deviation (SD) of 10, normed to the US population)] among non-Hispanic black (NHB), non-Hispanic white (NHW), and Hispanic elderly female patients, with newly diagnosed breast cancer (BC) between 2010-2015 in the Surveillance, Epidemiology and End Results-Medicare Health Outcomes Survey (SEER-MHOS) database (a cancer registry that provides value health-related quality of life information on patients enrolled in Medicare Advantage). The study analytic sample consisted of 11,765 NHW, 1,988 NHB and 1,361 Hispanic women with overall mean age and BMI of 50.1 years (SD: 10.5) and 27.5 kg/m^2 (SD: 6.6), respectively. Compared with NHW both NHB and Hispanic women had significantly elevated BMI [NHB risk difference (RD) 3.43, 95% CI: 3.09, 3.77; Hispanic RD 0.84, 95% CI: 0.44, 1.24]; but significantly lower age at diagnosis [NHB RD -2.86, 95% CI: -3.36, -2.37; Hispanic RD -1.67, 95% CI: -2.26, -1.09]. Compared with NHW, both crude PCS and MCS scores were significantly worse for NHB and Hispanic women [PCS: NHB RD -4.26, 95% CI: -4.87, -3.65; Hispanic RD -3.29, 95% CI: -4.01, -2.56; MCS: NHB RD -3.79, 95% CI: -4.37, -3.22; Hispanic RD -4.09, 95% CI: -4.76, -3.43]. These differences also persisted after adjustment for BMI and age [compared with NHW, PCS: NHB RD -2.09, 95% CI: -2.76, -1.43; Hispanic RD -3.26, 95% CI: -4.06, -2.45; MCS: NHB RD -3.2, 95% CI: -3.86, -2.54; Hispanic RD -4.21, 95% CI: -4.99, -3.43]. There were however no significant differences in PCS or MCS scores between NHB and Hispanic women after adjustment for age and BMI. Our results show that elderly NHB and Hispanic women with BC in the SEER-MHOS database are significantly more likely to have poorer physical and mental outcomes compared with NHW. However, this PRO disparity was not evident between NHB and Hispanic women and requires further exploration. Citation Format: Kendra R. Krebsbach, Chloe L. Stallion, Keith A. Dookeran. Examination of race/ethnicity differences in patient reported outcomes (PROs) among elderly female breast cancer patients in the SEER-MHOS database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5867.
Abstract 5076: Evaluation of the CNS penetration of a next generation PARP inhibitor, AZD9574, in cynomolgus monkey using positron emission tomography
Authors: Andy Pike, Amber Balazs, Zsolt Cselényi, Sébastien L. Degorce, Avipsa Ghosh, Sudhir M. Hande, Jeffrey Johannes, Peter Johnström, Martin J. Packer, Magnus Schou, XiaoLan Zheng
Journal: Cancer Research (2022)

Abstract The current clinically approved PARP inhibitors have limited subtype selectivity and are to some degree restricted in their ability to penetrate the central nervous system (CNS) due to efflux transporters, potentially limiting their efficacy in treating metastatic disease or primary tumors in the brain. The current study evaluated the potential of AZD9574, a next generation, PARP1 selective inhibitor/trapper, to penetrate the CNS in cynomolgus monkey, and its occupancy of the PARP1 enzyme, using positron emission tomography (PET). In vitro bidirectional efflux assay data suggested AZD9574 showed minimal substrate potential compared to the clinically approved PARP inhibitors. This was reflected in an increased ratio of unbound brain to unbound plasma concentration (Kpuu) in the rat of ~0.31. Therefore AZD9574 was taken forward into cynomolgus monkey PET studies. Firstly, the Kpuu was determined following dosing of [11C]AZD9574, co-administered with unlabeled drug to minimize the impact of specific binding. The high specific signal observed lead to the development of [11C]AZ3391, a PARP1 selective, CNS penetrant PET tracer, which was subsequently used to directly assess the PARP1 target engagement of AZD9574 in the brain. AZD9574 was found to show a Kpuu in cynomolgus monkeys of 0.79, close to unity with unbound plasma concentrations suggesting minimal CNS restriction. Furthermore, an i.v. infusion dose response study with AZD9574, conducted to examine its ability to block target occupancy by the PET tracer [11C]AZ3391, demonstrated a reduction in [11C]AZ3391 accumulation in whole brain. The resulting calculated occupancy of AZD9574 ranged from 17% for the lowest dose (0.003 mg/kg) to 95% for the highest dose tested (0.05 mg/kg). Comparable reduction in occupancy was seen for peripheral tissue, such as bone marrow, supporting the conclusion that AZD9574 shows minimal CNS restriction. These data show that AZD9574 is the first PARP inhibitor to reach the clinic which combines PARP1 selectivity, trapping and high CNS penetration in a single molecule and supports its development as a potential therapy for the treatment of metastatic disease and primary brain tumors. Citation Format: Andy Pike, Amber Balazs, Zsolt Cselényi, Sébastien L. Degorce, Avipsa Ghosh, Sudhir M. Hande, Jeffrey Johannes, Peter Johnström, Martin J. Packer, Magnus Schou, XiaoLan Zheng. Evaluation of the CNS penetration of a next generation PARP inhibitor, AZD9574, in cynomolgus monkey using positron emission tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5076.
Abstract 5849: Activation of STAT3 is mediated by FGFR4 induction via SRC signaling after <i>H. pylori</i> infection
Authors: Nadeem S. Bhat, Mohammed Soutto, Xing Zhang, Zheng Chen, Shoumin Zhu, Heng Lu, Dunfa Peng, Zekuan Xu, Wael El-Rifai
Journal: Cancer Research (2022)

Abstract Background: Gastric cancer is considered the 5th most common form of cancer and 4th leading cause of cancer-related deaths worldwide. Due to the late stage of diagnosis, gastric cancer carries poor prognosis and poor overall survival. Infection with H. pylori is the strongest known risk factor. Fibroblast Growth Factor Receptor 4 (FGFR4) belongs to a family of highly conserved tyrosine kinases. This study investigated the molecular mechanism of FGFR4 regulation in response to H. pylori infection. Methods and Results: Among all the FGFRs, FGFR4 mRNA expression level was the most significantly elevated in human gastric cancer samples as compared to normal samples, using Real-time qPCR. These results were confirmed using the TCGA and Geo database analysis, confirming that FGFR4 is highly expressed in gastric cancer. Using western blot, we found that FGFR4 is significantly expressed in dysplasia and adenocarcinoma lesions in the TFF1-KO gastric cancer mouse model. Following infection with H. pylori in in-vitro (J166, 7.13) and in-vivo (PMSS1) models, we detected a significant increase in the expression of FGFR4 at the protein and mRNA levels. We also detected activation of STAT3 in human gastric cell lines and mice gastric tissues. Furthermore, analysis of FGFR4 promoter revealed several putative binding sites for STAT3. To confirm that FGFR4 expression is dependent upon STAT3 activation, we performed ChIP assay and confirmed direct functional binding of STAT3 on FGFR4 promoter. Using the FGF19, the ligand for FGFR4, we found that FGF19-FGFR4 axis played a vital role in activating STAT3 through an SRC-dependent mechanism and discovered that there is a feedforward activation loop between FGFR4 and STAT3. Functionally, we found that FGFR4 protected against H. pylori-induced DNA damage and cell death. Conclusion: Our study established a feedforward activation loop between FGFR4 and STAT3 in response to H. pylori infection and FGFR4 could be a possible druggable moiety for future therapies in gastric cancer. Citation Format: Nadeem S. Bhat, Mohammed Soutto, Xing Zhang, Zheng Chen, Shoumin Zhu, Heng Lu, Dunfa Peng, Zekuan Xu, Wael El-Rifai. Activation of STAT3 is mediated by FGFR4 induction via SRC signaling after H. pylori infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5849.
Abstract 4153: First-in-class inhibitors of ERAP1 alter the HLA-I-restricted cancer immunopeptidome leading to the generation of novel peptides presented for immune recognition
Authors: Wayne Paes, Andrew Leishman, Kate Anderton, Hanqing Liao, Isaac Woodhouse, Robert Parker, Annalisa Nicastri, Peter Joyce, Nicola Ternette
Journal: Cancer Research (2022)

Abstract The antigen processing machinery of a cell shapes the repertoire of peptides presented for immune recognition on the cell surface. Human leukocyte antigen class I (HLA-I) molecules present peptides that are recognised by both CD8+ T cells and NK cells, and these complexes play a vital role in the recognition and eradication of malignant cells. During direct presentation, the endoplasmic reticulum aminopeptidase 1 (ERAP1) enzyme processes a subset of HLA-I ligand precursors which are translocated into the endoplasmic reticulum (ER) following intracellular proteasomal degradation. Here, we show that inhibition of ERAP1 with highly potent and selective small molecule inhibitors drives significant qualitative and quantitative changes in the HLA-I-restricted immunopeptidome, resulting in the generation of altered and novel peptides from tumour-associated antigens that are then presented on HLA-I molecules. A major consequence of inhibiting the processing of precursor ligands by ERAP1 within the ER of cancer cells was not only the generation of unique peptides which were not detectable under baseline conditions, but a shift in the peptide length distribution towards longer HLA-I-restricted peptides. Importantly, we demonstrate that the degree of bias towards longer HLA-I-bound ligands uniquely presented following ERAP1 inhibition was governed by both ERAP1 and HLA-I haplotypes. Such dramatic changes in the peptide repertoire presented for immune recognition have the potential to enhance anti-tumoural immunogenicity through T cell recognition of a novel cancer immunopeptidome, and, in addition to global shifts in the peptide length distributions, unique peptides presented for immune recognition during ERAP1 inhibition may be used as biomarkers for monitoring activity of this novel therapeutic approach in the clinic. Citation Format: Wayne Paes, Andrew Leishman, Kate Anderton, Hanqing Liao, Isaac Woodhouse, Robert Parker, Annalisa Nicastri, Peter Joyce, Nicola Ternette. First-in-class inhibitors of ERAP1 alter the HLA-I-restricted cancer immunopeptidome leading to the generation of novel peptides presented for immune recognition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4153.
Inhaled recombinant human IL-15 in dogs with naturally occurring pulmonary metastases from osteosarcoma or melanoma: a phase 1 study of clinical activity and correlates of response
Authors: Robert B Rebhun, Daniel York, Sylvia Margret Cruz, Sean J Judge, Aryana M Razmara, Lauren E Farley, Rachel V Brady, Eric G Johnson, Jenna H Burton, Jennifer Willcox, Luke A Wittenburg, Kevin Woolard, Cordelia Dunai, Susan L Stewart, Ellen E Sparger, Sita S Withers, Alicia A Gingrich, Katherine A Skorupski, Sami Al-Nadaf, Amandine T LeJeune, William TN Culp, William J Murphy, Michael S Kent, Robert J Canter
Journal: Journal for ImmunoTherapy of Cancer (2022)

Purpose Although recombinant human interleukin-15 (rhIL-15) has generated much excitement as an immunotherapeutic agent for cancer, activity in human clinical trials has been modest to date, in part due to the risks of toxicity with significant dose escalation. Since pulmonary metastases are a major site of distant failure in human and dog cancers, we sought to investigate inhaled rhIL-15 in dogs with naturally occurring lung metastases from osteosarcoma (OSA) or melanoma. We hypothesized a favorable benefit/risk profile given the concentrated delivery to the lungs with decreased systemic exposure. Experimental design We performed a phase I trial of inhaled rhIL-15 in dogs with gross pulmonary metastases using a traditional 3+3 cohort design. A starting dose of 10 µg twice daily × 14 days was used based on human, non-human primate, and murine studies. Safety, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) were the primary objectives, while response rates, progression-free and overall survival (OS), and pharmacokinetic and immune correlative analyses were secondary. Results From October 2018 to December 2020, we enrolled 21 dogs with 18 dogs reaching the 28-day response assessment to be evaluable. At dose level 5 (70 μg), we observed two DLTs, thereby establishing 50 µg twice daily × 14 days as the MTD and recommended phase 2 dose. Among 18 evaluable dogs, we observed one complete response &gt;1 year, one partial response with resolution of multiple target lesions, and five stable disease for an overall clinical benefit rate of 39%. Plasma rhIL-15 quantitation revealed detectable and sustained rhIL-15 concentrations between 1-hour and 6 hour postnebulization. Decreased pretreatment lymphocyte counts were significantly associated with clinical benefit. Cytotoxicity assays of banked peripheral blood mononuclear cells revealed significant increases in peak cytotoxicity against canine melanoma and OSA targets that correlated with OS. Conclusions In this first-in-dog clinical trial of inhaled rhIL-15 in dogs with advanced metastatic disease, we observed promising clinical activity when administered as a monotherapy for only 14 days. These data have significant clinical and biological implications for both dogs and humans with refractory lung metastases and support exploration of combinatorial therapies using inhaled rhIL-15.
Digital Breast Tomosynthesis and Detection of Interval Invasive and Advanced Breast Cancers
Authors: Sarah M. Friedewald, Lars J. Grimm
Journal: JAMA (2022)

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The Evolution of Diagnostic Technic
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal